The long-term goals of the research described in this submission are to provide a set of synthetic transformations for elaborating simple imidazoles into biologically relevant natural products and congeners. Two distinct projects are proposed that rely on mechanistically diverse reactions, but all involve, in one way or another, the disruption of the aromaticity of the imidazole ring. The first project seeks to develop the inter- and intramolecular Dieis-Alder reaction of 4-vinylimidazoles as a means to construct polycyclic molecules that may be useful en route to natural products, in particular the oroidin derived pyrroloimidazole class of compounds isolated from marine sponges. This reaction is expected to feature as the key step in the assembly of a number of targets including the Agelas alkaloids (e.g., ageliferin), which possess antibacterial properties, and the more complex palau'amine and related targets, konbu'acidin A, styloguanidine and axinellamine A. Palau'amine, a hexacyclic, bisguanidine-containing alkaloid, is a potent immunosuppressant, exhibiting a nanomolar IC50 in the mixed lymphocyte reaction. Furthermore, palau'amine showed significant activity against P-388 and A-549 cancer cell lines, with IC50's of 0.2 and 0.5 fM respectively. The related acylated congener, konbu'acidin A, inhibits cyclin dependent kinase 4 and thus may prove useful as an anti-cancer lead, whereas styloguanidine is a chitinase inhibitor. The second project will focus on the recently discovered dimethyldioxirane induced oxidative rearrangement of bicyclic imidazoles (tetrahydrobenzimidazoles) to spiro imidazolones. It is proposed to investigate the scope and limitations of this potentially important reaction. In particular, the influence of both imidazole substituents on nitrogen and at C2 will be investigated along with the role of peripheral substituents at C4 and C5 on the stereochemical outcome of the rearrangement. It is anticipated that this reaction will play a pivotal role in approaches to palau'amine, konbu'acidin A, styloguanidine and axinellamine A. Also, it is planned to establish the applicability of the rearrangement to imidazo[4,5-b]pyridines, if successful, the rearranged products might function as key intermediates in approaches to several monomeric oroidin-derived alkaloids, such as phakellin, saxitoxin and cantharelline. The final projects will apply the methodology developed during the exploratory phases of this program to a number of the dimeric oroidin-derived marine alkaloids (i) ageliferin, (ii) axinellamine A, (iii) palau'amine, (iv) konbu'acidin A and (v) styloguanidine.